Classifications

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  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
  • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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  • C07D209/04—Indoles; Hydrogenated indoles
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Definitions

• the present invention relates to new substituted cyclic compounds having very valuable pharmacological characteristics in respect of melatoninergic receptors.
• the prior art discloses thio-substituted indole amides for use as anti-inflammatory agents (EP 624575, EP 535923), as antagonists of the release of gonadotrophin (WO 9721703), as 5HT-2B or 2C antagonists (WO 9602537), or as synthesis intermediates (Akad. Nauk Gruz., 1991, 141 (3), pp. 545-8; Pept. Chem., 1993, 31, pp. 33-6, J. Pharm. Sci., 1973, 62 (8), pp. 1374-5).
• Benzo[b]thiophene compounds have also been described as anti-inflammatory agents (U.S. Pat. Nos. 5,350,748, 5,068,248) or as anti-cancer agents (Heterocycles, 1985, 23 (5), pp. 1173-80).
• melatonin (5-methoxy-N-acetyltryptamine) in numerous physiopathological phenomena and also in the control of circadian rhythm. Its half-life is, however, quite short owing to its being rapidly metabolised. It is thus very useful to be able to provide the clinician with melatonin analogues that are metabolically more stable and that have an agonist or antagonist character on the basis of which a therapeutic effect that is superior to that of the hormone itself may be expected. In addition to their beneficial action on disorders of circadian rhythm (J. Neurosurg.
• ligands of the melatoninergic system have valuable pharmacological properties in respect of the central nervous system, especially anxiolytic and antipsychotic properties (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp 264-272) and analgesic properties (Pharmacopsychiat., 1987, 20, pp 222-223), and also for the treatment of Parkinson's disease (J. Neurosurg. 1985, 63, pp 321-341) and Alzheimer's disease (Brain Research, 1990, 528, pp 170-174).
• the compounds of the present invention exhibit very great affinity for melatonin receptors and/or selectivity for one or other of the melatoninergic receptor sub-types.
• hydrochloric acid hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid etc.
• Preferred compounds of the invention are those wherein A represents a ring system of formula (II) or (III) and, more especially, of formula (II′): wherein B, X and the symbol .... are as defined hereinbefore, or of formula (III′) wherein B′, T′, X′ and the symbol ... are as defined hereinbefore.
• the invention advantageously relates to compounds wherein A, which is unsubstituted or substituted by a single substituent (in addition to R and R′) preferably in the 2-position (formula II′) or in the 3-position (formula III′), represents a ring system of formula (II′): wherein B, X and the symbol .... are as defined hereinbefore, such as, for example, benzothiophene, dihydrobenzothiophene, benzofuran, dihydrobenzofuran, indole, indoline, indan, indene, azaindole, thienopyridine or furopyridine, or of formula (III′): wherein B′, T′, X′ and the symbol ....
• naphthalene tetrahydronaphthalene
• thiochroman naphthalene, tetrahydronaphthalene
• dihydro benzodioxin
• dihydro benzoxathiin
• dihydro benzochromene
• the invention relates to compounds wherein A of formula (II′) or (III′) is substituted by R in the 5-position (formula II′) or 7-position (formula III′) and by R′ in the 3-position (formula II′) or 1- or 2-position (formula III′).
• Preferred substituents R of the invention are those represented by a group of formula (V), (VI) or —NR′ a R′′ a (wherein R′ a and R′′ a are as defined hereinbefore).
• preferred substituents R of the invention are those represented by a group of formula (V) (wherein r is 0 and R 1 represents a group R a as defined hereinbefore), a group NR′ a R′′ a (wherein R′ a and R′′ a are as defined hereinbefore), or a group of formula (VI) wherein E represents a group wherein r and R a are as defined hereinbefore.
• R of the invention are those represented by a group of formula (V) wherein r is 0 and R 1 represents an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycl
• R′ of the invention are those wherein G represents an unsubstituted or substituted alkylene chain —(CH 2 ) t —, wherein t is 2 or 3, and R 2 represents a group wherein R a , R′ a and R′′ a are as defined hereinbefore.
• R′ of the invention are those wherein G represents a group —(CH 2 ) t —, wherein t is 2 or 3, and R 2 represents a group wherein R′ a represents an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclo
• preferred compounds of the invention are those wherein A represents a ring system of formula (II′) or (III′) and R represents a group of formula (V), (VI) or —NR′ a R′′ a .
• the invention relates to compounds wherein:
• preferred compounds of the invention are those wherein
• the invention relates to (dihydro)benzothiophenes, (dihydro)benzofurans, indoles, indolines, indenes, indans, azaindoles, thieno- or furopyridines optionally substituted in the 2-position, and to dihydronaphthalenes, tetrahydronaphthalenes, naphthalenes or chromans optionally substituted in the 3-position, substituted in the 5-position (or 7-position, respectively) by a group —SR a or —NR′ a R′′ a wherein R′ a and R′′ a , which may be the same or different, represent a hydrogen atom, an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl
• preferred compounds of the invention are naphthalenes, optionally substituted in the 3-position, substituted in the 7-position by a thioalkyl group such as, for example, thiomethyl, thioethyl, thiopropyl, and substituted in the 1-position by a group —(CH 2 ) t —NHCOR′ a wherein t is 2 or 3 and R′ a represents an alkyl, polyhaloalkyl or cycloalkyl group, such as, for example, methyl, ethyl, propyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
• a thioalkyl group such as, for example, thiomethyl, thioethyl, thiopropyl
• R′ a represents an alkyl, polyhaloalkyl or cycloalkyl group, such as, for example, methyl,
• the invention relates very particularly to the compounds of formula (I) that are:
• the invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material the compound of formula (VIII): wherein A and R′ are as defined hereinbefore, which is subjected to demethylation using conventional agents such as HBr, AlCl 3 , AlBr 3 , BBr 3 or Lewis acid/nucleophile binary systems such as AlCl 3 /PhCH 2 SH, or BBr 3 /Me 2 S, for example, to obtain the compound of formula (IX): HO—A—R′ (IX) wherein A and R′ are as defined hereinbefore,
• the starting compounds (VIII) are either commercially available or are described in the literature, for example in the Patent Applications EP0447285, EP0527687, EP0562956, EP0591057, EP0662471, EP0745586, EP0709371, EP0745583, EP0721938, EP0745584, EP0737670, EP0737685, or WO9738682.
• the invention relates also to a process for the preparation of compounds of formula (I) wherein R represents a ring of formula (VI), which process is characterised in that compounds of formulae (I/a) to (I/i) are used as starting materials, which are cyclised according to methods described in the literature, for example in the Patent Applications EP0708099 or WO9732871.
• the compounds of the invention and pharmaceutical compositions comprising them are proving to be useful in the treatment of disorders of the melatoninergic system.
• the invention relates also to the compounds of formula (XX A ), a particular case of the compounds of formula (XX): Hal—A A —R′ A (XX A ) wherein:
• the compounds will preferably be used in the treatment of seasonal affective disorder, sleep disorders, cardiovascular pathologies, insomnia and fatigue resulting from jet lag, appetite disorders and obesity.
• the compounds will be used in the treatment of seasonal affective disorder and sleep disorders.
• the present invention relates also to pharmaceutical compositions comprising at least one compound of formula (I), alone or in combination with one or more pharmaceutically acceptable excipients.
• compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration and especially tablets, dragees, sublingual tablets, sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules.
• the dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possible associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in 1 or more administrations.
• Succinic anhydride (17 g, 170 mmol) is added to a solution of thioanisole (20 ml, 170 mmol) in 140 ml of tetrachloroethane and the reaction mixture is then brought to 0° C. Aluminium trichloride (45.43 g, 341 mmol) is added in portions and the reaction mixture is then heated at 60° C. for 3.00 hours. After cooling and hydrolysis in the presence of ice-cold water (500 ml) and concentrated hydrochloric acid (50 ml), the white precipitate formed is filtered off, rinsed with water and recrystallised from ethyl acetate to yield the desired acid.
• Step B 4-[4-(Methylthio)phenyl]butanoic acid
• Step B the acid obtained in Step B (10 g, 52 mmol) is heated at 70° C. for 2 hours in the presence of 10 times as much, by weight, polyphosphoric acid (100 g).
• the reaction mixture is hydrolysed in ice and is then extracted with ethyl ether.
• the organic phase is washed with water, dried over magnesium sulphate and evaporated.
• the residue is purified by chromatography on silica gel (eluant: dichloromethane) to yield the expected tetralone in the form of a yellow oil.
• Step D 2-[7-(Methylthio)-1,2,3,4-tetrahydro-1-naphthalenylidene]acetonitrile
• diethyl cyanomethylphosphonate (7.6 ml, 46.8 mmol) is added dropwise to a suspension of sodium hydride (2.25 g, 46.8 mmol) in 50 ml of tetrahydrofuran. Stirring is carried out at 0° C. for 30 minutes; the compound obtained in Step C (6 g, 31.2 mmol), dissolved in 50 ml of tetrahydrofuran, is then added and the reaction mixture is stirred at ambient temperature for 3 hours. After hydrolysis and extraction with ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on silica gel (eluant: petroleum ether/dichloromethane 50/50) to yield the unsaturated nitrile of the title.
• silica gel eluant: petroleum ether/dichloromethane 50/50
• Step D The compound obtained in Step D (2 g, 9.29 mmol) is heated at 230° C. in the presence of sulphur (357 mg, 11.1 mmol) for 16 hours. After hydrolysis and extraction with ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on silica gel (eluant: cyclohexane/ethyl acetate 80/20) to yield the corresponding aromatic compound in the form of a beige solid.
• Step F 2-[7-(Methylthio)-1-naphthyl]-1-ethylamine hydrochloride
• Step E Under an inert atmosphere, the compound obtained in Step E (1.93 g, 9.04 mmol), previously dissolved in 30 ml of tetrahydrofuran, is added to a 1M solution of borane in tetrahydrofuran (27.1 ml, 22.1 mmol) and the reaction mixture is then heated at reflux for 3 hours. A 6N hydrochloric acid solution (18 ml, 108 mmol) is then added very slowly and stirring is carried out at reflux for 30 minutes more. After extraction with ethyl acetate, the aqueous phase is rendered alkaline with 16% sodium hydroxide solution and is then extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and evaporated.
• the residue is purified by chromatography on silica gel (eluant: dichloromethane/methanol 50/50 and then methanol/ammonium hydroxide 95/5) to yield the expected amine.
• the amine is taken up in ethyl ether; ethyl ether saturated with gaseous hydrogen chloride is then added dropwise and the precipitate obtained is filtered off to yield the corresponding hydrochloride in the form of a white solid.
• Chlorine (10 mmol) is bubbled into dichlorophenylphosphine at a flow rate such that the reaction temperature is maintained between 70 and 80° C. After all the chlorine has been added, the phenylphosphine tetrachloride so obtained is a pale yellow liquid. 10 mmol of the product obtained in Preparation 5 are added all at once and the reaction mixture is heated at 160° C. overnight. After cooling, the solution is poured into a water/ice mixture (20 ml) and is neutralised with a 50% aqueous solution of sodium hydroxide. After extraction with ether, the organic phases are dried and concentrated under reduced pressure to yield a residue, which is chromatographed on silica gel to obtain the pure title product.
• Triphenylphosphine (10 mmol) and acetonitrile (70 ml) are poured into a 150 ml three-necked flask equipped with a bromine funnel, a condenser surmounted by a tube filled with calcium chloride and a mechanical stirrer.
• the solution is cooled with the aid of an ice bath, with stirring, and bromine is added (10 mmol).
• the ice bath is removed and the product obtained in Preparation 3 (8 mmol) is then added.
• the reaction mixture is stirred at 60-70° C. until the starting compound has disappeared (monitored by TLC). At the end of the reaction, the mixture is filtered and the filtrate is then concentrated under reduced pressure.
• Preparations 161 to 185 the procedure is as in Preparation 160, but the product of Preparation 134 is replaced by the appropriate substrate.
• Step A In a 100 ml round-bottomed flask, 1 eq. of the compound obtained in Step A, 10 eq. of polyphosphoric acid and 1 eq. of phosphoric anhydride are mixed together. The mixture is stirred for 3 hours at 180° C. and is then hydrolysed. Extraction with ether is carried out, and the organic phase is washed with water, dried over MgSO 4 and evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica gel column.
• Step B 1 eq. of the compound obtained in Step B is dissolved in 20 ml of CCl 4 . 1 eq. of N-bromosuccinimide and 0.04 eq. of benzoyl peroxide are then added, and the mixture is irradiated by means of a halogen lamp and maintained at reflux for 4 hours. At the end of the reaction, the insoluble material is filtered off, and the carbon tetrachloride is evaporated off. The residue obtained is purified by chromatography on a silica gel column.
• Step E 2-(5-Chloro-2-phenyl-1-benzothiophen-3-yl)-1-ethanamine hydrochloride
• Step D 3 eq. of diborane in tetrahydrofuran and 1 eq. of the nitrile obtained in Step D are introduced into a 100 ml round-bottomed flask, and the mixture is then heated at reflux for 2 hours. After cooling, 15 eq. of 6M HCl are added and the tetrahydrofuran is evaporated off under reduced pressure. The precipitate formed is filtered off and recrystallised.
• Step E The compound obtained in Step E is dissolved in a mixture of water/dichloromethane (2/3); 2 eq. of potassium carbonate are then added and 2 eq. acetyl chloride are added dropwise. After stirring for 2 hours at ambient temperature, the 2 phases are separated; the organic phase is washed with 1M HCl and then with water, until the washing waters are neutral, and is then dried as over MgSO 4 and evaporated. The residue obtained is purified by chromatography on silica gel.
• Preparations 225 to 235 are obtained by proceeding as in Preparation 224.
• Preparations 236 to 238 are obtained by proceeding as in Preparation 134.
• Step A 0.092 mol of the compound obtained in Step A is dissolved in is 200 ml of methanol The mixture is cooled using an ice bath and 0.138 mol of thionyl chloride is added dropwise. The reaction mixture is stirred for 5 hours at ambient temperature; the methanol is then evaporated off and the solid obtained is taken up in petroleum ether, filtered off under suction and used directly in the following Step.
• Step B 0.095 mol of the compound obtained in Step B is dissolved in 250 ml of methanol. 1 g of 10% activated palladium-on-carbon is added and magnetic stirring is carried out under a hydrogen atmosphere for 12 hours. The palladiated carbon is then filtered off, and the methanol is evaporated off under reduced pressure. The oil obtained is purified by chromatography on silica gel.
• Step C 0.076 mol of the compound obtained in Step C is introduced in a 500 ml round-bottomed flask, and then 250 ml of water and 0.152 mol of NaOH are added. The reaction mixture is stirred for 12 hours at ambient temperature. The reaction mixture is then acidified with 3M HCl and is extracted twice with ethyl ether. The organic phase is dried over MgSO 4 and evaporated under reduced pressure to obtain the title product in the form of a white solid.
• Step D 0.055 mol of the compound obtained in Step D is introduced into a 500 ml round-bottomed flask together with 100 g of polyphosphoric acid.
• the reaction mixture is heated at 60° C. for 4 hours.
• the mixture is then cooled and poured into water; the precipitate formed is then dried and recrystallised.
• Step F 2-[7-Fluoro-3,4-dihydro-1(2H)-naphthalenylidene]acetonitrile
• 1.6 eq. of Nal are suspended in 130 ml of anhydrous THF under a nitrogen atmosphere in a 250 ml three-necked flask.
• the mixture is cooled in a bath of ice/salt and 1.6 eq. of diethyl cyanomethylenephosphonate in 40 ml of THF are added dropwise.
• the reaction mixture is stirred for 45 minutes and then, whilst still cold, 1 eq. of the compound obtained in Step E, in 70 ml of THF, is added dropwise.
• the mixture is stirred for 4 hours and is then poured onto a mixture of ice/water, acidified with 3M HCl solution and extracted 3 times with ethyl ether.
• the organic phase is dried over MgSO 4 and evaporated under reduced pressure; the residue obtained is recrystallised.
• Step G 2-(7-Fluoro-1,2,3,4-tetrahydro-1-naphthyl)-1-ethylamine hydrochloride
• Step F 0.011 mol of the compound obtained in Step F is dissolved in 100 ml of 95° alcohol and introduced into a 400 ml autoclave; 0.5 g of Raney nickel is then added. The solution is saturated with ammonia gas, and hydrogen is introduced until a pressure of 50 bars is obtained. The reaction mixture is stirred for 5 hours at 60° C. and is then cooled, filtered and evaporated under reduced pressure. The oil obtained is dissolved in anhydrous ethyl ether and a solution of ethyl ether saturated with gaseous hydrogen chloride is added dropwise. The precipitate formed is filtered off under suction and recrystallised.
• Step H N-[2-(7-Fluoro-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide
• Preparations 247 to 257 are obtained by proceeding as in Preparation 224.
• the residue is purified by chromatography on silica gel (eluant: acetone/toluene/cyclohexane 30/50/20) and is then recrystallised from a mixture of cyclohexane and toluene to yield the title acetamide in the form of a white solid.
• methyl isocyanate (2.20 mmol) is added to a solution of the product obtained in Preparation 1 (1.84 mmol) in 8 ml of pyridine. Stirring is carried out for 16 hours at ambient temperature and the reaction mixture is then hydrolysed and subsequently extracted with ethyl acetate. The organic phase is washed with 3N hydrochloric acid solution and then with water, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on silica gel (eluant: acetone/toluene/cyclohexane 40/40/20) and is then recrystallised from toluene to yield the title product in the form of a white solid.
• benzoyl chloride (4.44 mmol) is added dropwise to a suspension of aluminium trichloride (7.40 mmol) in 15 ml of dichloromethane.
• the reaction mixture is stirred at 0° C. for 30 minutes; the compound obtained in Example 1, dissolved in 10 ml of dichloromethane, is then added dropwise and stirring is continued for 16 hours.
• the two phases are separated; the organic phase is washed with water, dried over magnesium sulphate and evaporated.
• the diphenyl ether is evaporated off under reduced pressure until a solution of approximately 2 ml is obtained.
• the 2 ml of distillate, whilst still hot, are poured with caution into 50 ml of hexane to yield, after cooling, a solid that is isolated by filtration.
• the solid thus collected is added to a solution of potassium hydroxide (380 mg) dissolved in a mixture of water/methanol (1 ml/10 ml).
• the solution is heated at reflux for 12 hours and is then cooled and concentrated under reduced pressure.
• the residue is taken up in 20 ml of chloroform and is extracted 3 times with water.
• the organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure.
• the residue is chromatographed on silica gel to yield the title product.
• Examples 11 to 36 are obtained by proceeding as in Example 10, starting from the appropriate hydroxylated compound.
• Example 37 to 170 the procedure is as in Example 8, but the ethanethiol is replaced by the appropriate thiol and the N-[2-(7-hydroxy-1-naphthyl)ethyl]acetamide by the appropriate hydroxylated compound.
• Example 43 The product obtained in Example 43 (10 mmol) is added to an aqueous 0.5M sodium periodate solution (21 ml, 10.5 mmol) at 0° C. Stirring at 0-5° C. is carried out overnight. The solution is filtered and the filtrate is extracted with chloroform. The organic phase is dried over magnesium sulphate and is concentrated under reduced pressure. The residue is chromatographed on silica gel to yield the title compound.
• Example 172 to 184 the procedure is the same as in Example 171, starting from the appropriate thioether.
• Example 39 The product obtained in Example 39 (10 mmol) is dissolved in 40 ml of methanol and is cooled to 0° C. with the aid of an ice bath. A 49.5% solution of KHSO 5 (30 mmol) in water (40 ml) is added. Stirring is carried out for 4 hours at ambient temperature. The reaction mixture is then diluted with water and extracted 3 times with chloroform. The organic phases are combined, washed with water and with saturated NaCl solution and then dried over Na 2 SO 4 and concentrated under reduced pressure. The title product is obtained after chromatography on silica gel.
• Examples 186 to 193 are obtained by proceeding as in Example 185, starting from the corresponding thioether.
• Polyphosphate ester (20 ml) is added to a mixture of propanoic acid (30 mmol) and the product obtained in Example 10 (31 mmol) and the reaction mixture is stirred for 15 hours at ambient temperature. The mixture is then treated with saturated aqueous sodium hydrogen carbonate solution (200 ml) and is extracted with chloroform (3 ⁇ 30 ml). The organic phases are combined, dried over magnesium sulphate and then concentrated under reduced pressure. The residue is chromatographed on silica gel to yield the title product. (Polyphosphate ester is prepared according to the method described by W. Pollmann et al., Biochem. Biophys. Acta, 80 (1), 1964).
• Examples 195 to 204 are prepared according to the procedure of Example 194, starting from appropriate reactants.
• Example 206 to 209 the procedure is as in Example 205, starting from appropriate reactants.
• Step A Ethyl 2- ⁇ [8-[4-(cyclohexylamino)-4-oxobutyl]-2-naphthyl]sulphanyl ⁇ -3-oxo-butanoate
• Example 13 Sodium (34 mmol) is added, with vigorous stirring, over a period of one hour, to a boiling solution of the product obtained in Example 13 (34 mmol) in 70 ml of anhydrous xylene. Stirring is continued, under reflux, for 2 hours and the mixture is allowed to cool to approximately 80° C. Ethyl chloro-2-acetylacetate (38 mmol) is then added dropwise. The mixture is then heated at reflux again for one hour. After cooling, the organic phase is washed with water, dried and concentrated to dryness under reduced pressure to yield the title product.
• Step B Ethyl 9-[4-(cyclohexylamino)-4-oxobutyl]-1-methylnaphtho[2,1-b]thiophene-2-carboxylate
• Example 211 to 215 the procedure is as in Example 210, starting from appropriate reactants.
• Example 171 The procedure is as in Example 171, starting from Example 211.
• Example 185 The procedure is as in Example 185, starting from Example 212.
• Step A Ethyl 3- ⁇ [8-(2- ⁇ [3-(trifluoromethyl)benzoyl]amino ⁇ ethyl)-2-naphthyl]sulphanyl ⁇ propanate
• Step B 3- ⁇ [8-(2- ⁇ [3-(Trifluoromethyl)benzoyl]amino ⁇ ethyl)-2-naphthyl]sulphonyl ⁇ propanoic acid
• Step A A 0.5N aqueous solution of K 2 CO 3 (10 ml) is added to the product obtained in Step A (4 mmol) dissolved in methanol (10 ml). When the reaction has ceased, the solution is acidified to pH 6 using 1N HCl solution. The reaction mixture is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulphate, concentrated under reduced pressure and chromatographed on silica gel to yield the title product.
• Step C 3- ⁇ [8-(2- ⁇ [3-(Trifluoromethyl)benzoyl]amino ⁇ ethyl)-2-naphthyl]sulphonylpropanoyl chloride
• Step B The product obtained in Step B (3 mmol), dissolved in thionyl chloride, is stirred at 60° C. under a current of nitrogen for one hour.
• the thionyl chloride is evaporated off under reduced pressure and the residue is dried with the aid of a vane pump to yield the title product.
• Step D N-[2-(1-Oxo-2,3-dihydro-1H-benzo[f]thiochromen-10-yl)ethyl]-3-(trifluoromethyl)benzamide
• Step C The product obtained in Step C (3 mmol), dissolved in 1,1,2,2-tetrachloroethane (30ml), is poured dropwise into a solution of aluminium chloride (10 mmol) in the same solvent (20 ml) under nitrogen.
• the reaction mixture is heated at 60° C., with stiffing, until the reaction has ceased.
• the solution is then poured into a mixture of ice (10 g) and concentrated HCl (0.3 ml) and stirring is carried out for one hour.
• the aqueous phase is extracted with chloroform (twice); the combined organic phases are then dried over magnesium sulphate, concentrated under reduced pressure and then chromatographed on silica gel to yield the title product.
• Example 219 to 2208 the procedure is as in Example 218, but the appropriate thiol and Preparation are used to obtain the title compound.
• Example 218 The compound of Example 218 (3 mmol) is dissolved in acetic acid (70 ml) and, after several purges with argon, 10% palladiumon-carbon (600 mg) is added and the mixture is placed under a hydrogen atmosphere. Stirring is carried out at ambient temperature until the reaction is complete and the palladium is filtered off over Celite. The acetic acid is evaporated off to dryness and the residue is chromatographed on silica gel to yield the title product.
• Example 230 to 235 the procedure is as for Example 229, but the product of Example 218 is replaced by the appropriate reactant.

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